Calibratable sensor unit for reaction vessels

ABSTRACT

The invention relates to a reaction vessel with a sensor unit. The reaction vessel comprising a reaction space configured to be connected with the sensor unit that comprises at least one sensor device configured to be calibrated, at least one compartment containing a calibrating agent, and a housing. The sensor unit is arranged to calibrate the at least one sensor device by contact with the calibrating agent before chemical or physical parameters of a measurement substance are measured, wherein the at least one sensor device is further configured such that the relative movement between the at least one sensor device and the at least one compartment is irreversible. The at least one sensor device is movable relative to the at least one compartment from an initial position into a measurement readiness position. The reaction vessel and the sensor unit can be sterilised or are sterilised jointly.

This application is a divisional of U.S. Ser. No. 13/024,662 filed Feb.10, 2011, which claims the benefit of German Patent Application No. 102010 001 779.5 filed on Feb. 10,2010, the disclosures of which areincorporated herein in their entirety by reference.

The present invention relates to a calibratable sensor unit for areaction vessel, such as for example a fermenter, in particular adisposable (single-use) fermenter, comprising at least one sensor deviceto be calibrated and at least one compartment containing a calibratingagent, the at least one sensor device and the at least one compartmentbeing accommodated movably relative to one another in a housing that isconnected to or can be connected to the reaction vessel, wherein thesensor unit is arranged so as to calibrate the at least one sensordevice by contact with the calibrating agent before chemical and/orphysical parameters of a measurement substance are measured with the atleast one sensor device.

Such a sensor unit is known for example from EP 0 372 121 B1. The sensordevice illustrated there can be introduced in the axial direction of ahousing-type sleeve accommodating it into a fermenter and can bewithdrawn from the latter. The sensor device has at its end to beintroduced into the fermenter a sensitive element as well as a type ofcover, by means of which the sleeve can be hermetically sealed withrespect to the interior of the fermenter when the sensor device isretracted. When the sensor device has been fully inserted into thesleeve and thus sealed with respect to the fermenter, a cleaning agentor a calibrating agent can be introduced into the sleeve by means offeed inlets mounted on the sleeve, so that the sensitive element of thesensor device can be rinsed without the cleaning agent or calibratingagent being able to pass into the fermenter. By arranging three sealingrings that are disposed at predetermined spacings relative to oneanother in the axial direction, a type of sluice function can beimplemented in co-operation with various internal peripheral walls ofdifferent diameters. This sluice function allows that, depending on therelative position of the sensor device to the surrounding housing, thecleaning agent or calibrating agent can rinse different regions in theinterior of the calibrating unit. The sensor proposed in EP 0 372 121 B1is reusable and can be used multiple times. Furthermore it is alsoreplaceably accommodated in the sleeve and/or housing of the calibratingunit.

From U.S. Pat. No. 5,939,610 a measuring device is further known with asensor that can be ejected from a sleeve-type housing. The sensor isstored in calibrating fluid in a compartment. In order to be able toeject the sensor in the axial direction from the surrounding sleeve, themeasuring device has to be rotated so that the end at which the sensorwill exit is aligned substantially vertically upwards. This alignment ofthe measuring device is necessary since otherwise calibrating fluidwould flow out of the compartment during the ejection procedure of thesensor. The sensor can be multiply actuated by means of a spring-detentmechanism, similar to an actuation device in a ballpoint pen. When thesensor or its sensitive element has been ejected sufficiently far fromthe housing that a measurement can be carried out, the opening throughwhich the sensor has exited and which can be closed and sealed by aswivellable cover is closed by the co-operation of the outercircumference of the sensor device and the inner circumference of theopening edge, so that no calibrating agent can escape during themeasurement procedure. On account of the possible multiple use andactuation of the sensor there is the danger with such a measuring devicethat impurities adhering to the sensitive element of the sensor can passinto the calibrating fluid. This is furthermore promoted by the factthat also when retracting the sensor into the compartment withcalibrating fluid the measuring device has to be held in the verticallyupwardly aligned position described above.

In biotechnology and especially also in the pharmaceutical industry theuse of so-called disposable fermenters has increased. Known steelreactors are increasingly being replaced by disposable fermenters madeof plastics material. An example of such a disposable fermenter systemis disclosed inter alia in US 2005/0239199 A1.

The use of disposable fermenters leads to large time and cost savings,since expensive and complicated cleaning steps such as clean in process(CIP) and sterilisation in process (SIP), which are a necessary measurein the case of steel reactors in order to sterilise the steel fermenterfor the next culture, can be omitted. A further advantage of disposablefermenters compared to conventional steel reactors is the exclusion ofthe risk of cross-contamination, since disposable fermenters aresterilised before use.

In order to be able to measure chemical and physical parameters in thefermentation mixture when using disposable fermenters, such as forexample pH value, conductivity, dissolved oxygen, cell density, opticaldensity, pressure, carbon dioxide content and other substanceconcentrations, corresponding sensors, in particular physical, chemical,electrochemical and/or optical, must also be provided on disposablefermenters. A precondition for the use of sensors in disposablefermenters however is that these have to be introduced into the reactionspace (interior) of a disposable fermenter without contaminating thelatter during the introduction. In this connection ease of handling, lowcosts and the ability to calibrate the sensors as simply as possible butnevertheless accurately, are desirable.

Various systems have been proposed for introducing chemical sensors intothe reaction space of disposable fermenters. For example opticalpatches, such as polymer membranes in which optically active substancesare immobilised, are integrated in a wall of the disposable fermenter.The optically active substances immobilised in the patches change theirfluorescence signals for example depending on the partial pressure ofthe dissolved oxygen or the pH-value of the fermentation mixture, whichcan be measured and evaluated with corresponding excitation anddetection devices mounted externally on the disposable fermenter. Anexample of such optical systems is disclosed in DE 101 37 530 A1 or US2008/0032389 A1. A problem in the use of such patches is, apart from thelimited choice of sensors, the low stability, for example in the case ofpH-sensitive patches, of the employed optically active substances toγ-rays, which are used in the sterilisation. Since less “hard”irradiation with UVC- and β-rays is often too weak on account of theirlow penetration depth of only a few tenths of a millimetre, disposablefermenters are normally irradiated with γ-rays at circa 50 kGrey forsterilisation purposes. Furthermore, with such patches there is thedanger that their optically active substances, which are generally toxicand carcinogenic, are released into the fermenter and as a result thecontents are contaminated. Further problems arise due to the uncertaintyconcerning the long-term stability of the patches on account of ageingand the associated questionable quality of the preliminary calibration,so that in practice the external measurement of a sample taken from thedisposable fermenter and a subsequent adjustment of the sensor systemare as a rule necessary.

On account of their higher accuracy, sensory versatility, their largermeasurement range and their greater robustness, it is desirable thatalso traditional sensors, such as for example the pH single-rodmeasuring chain, can be used also in disposable fermenters. Systems inwhich the sensor is integrated in the reactor, so that both can besterilised together, represent one possibility of using traditionalsensors in disposable fermenters. In this connection reference is madefor example to WO 2009/059645 A1. The device proposed there permits inaddition an end-point calibration, by integrating a pH sensor in avessel together with a γ-sterilisable and pH-stable storage solution,which also serves as calibrating solution for an end-point calibrationand is combined with the disposable fermenter. However, an end-pointcalibration is not sufficient for an accurate pH measurement withcommercial pH sensors. Deviations of up to 0.25 pH units can occur.Since the storage solution and calibrating solution in the proposedsystem likewise reach the reaction space (interior of the fermenter)when the sensor is introduced, this can lead to a contamination of thefermentation mixture, especially with small fermenter volumes.

The object of the invention is to provide a calibratable sensor unitthat enables a sensor to be calibrated accurately and reliably understerile conditions and in a simple way. In this connection the sensoryprinciple of the sensor that is used is not important.

In order to achieve this object it is proposed that a generic sensorunit is modified in such a way that the relative movement between the atleast one sensor device and the at least one compartment can be carriedout irreversibly, the at least one sensor device being movable relativeto the at least one compartment from an initial position, in which thesensor device when correctly used cannot be contacted by the measurementsubstance, under a change of the surroundings of at least a part of thesensor device, in particular of a sensitive element, to a measurementreadiness position different from the initial position, in whichreadiness position the sensor device can be contacted at leastpartially, in particular with a sensitive element, by the measurementsubstance.

Since the movement of the sensor device, in particular its sensitiveelement, cannot be reversed from the initial position back to themeasurement readiness position, the sensitive element of the sensordevice can be moved relative to the at least one compartment by means ofan unambiguous and defined procedure. In this way a simple anderror-free handling and manipulation can be ensured.

A reaction vessel is understood to mean any vessel in which ameasurement substance is subjected to changes on account of chemicaland/or biological reactions and/or on account of ageing. In thisconnection the changes can be monitored by sensors and if necessaryinterventions can be carried out in the reaction taking place in thereaction vessel.

By means of a preferred automatic holding of the sensor device in themeasurement readiness position it is ensured that the sensitive elementonce it has been introduced into a reaction space of the reaction vessel(fermenter interior) remains there and can no longer be retracted intothe housing of the calibrating unit. The danger of impurities andcontamination is thereby reduced to a minimum or even prevented.Preferably the sensor device can be locked, in particular in anirreversible manner, in the measurement readiness position.

The housing of the sensor unit preferably surrounds the at least onesensor device in the initial position and the at least one compartment.In this way the sensor device and the compartments can be protectedagainst external contamination.

In the initial position the sensor device, in particular its sensitiveelement, can be accommodated in an associated compartment withcalibrating agent. This ensures that the sensitive element can be storedin a chemically favourable environment before it is actually used in thefermenter interior.

In order to be able to seal the at least one compartment, it can beclosed by at least one septum. In this connection the compartment can beseparated by means of the septum in particular from the interior of thesensor unit surrounded by the housing or from an adjacent compartment orfrom the fermenter. Preferably the at least one septum is prepared sothat it can easily be penetrated or punctured by means of the sensordevice. In particular the septum can comprise regions of differentmaterial thickness and/or can be perforated at least in part. In thiscase a perforation can completely penetrate the septum material or canhowever be implemented as a partial perforation, i.e. with at least oneopening that does not extend over the whole material thickness of theseptum. In order to be able to introduce the sensitive element of the atleast one sensor device into the at least one compartment, it isproposed in this connection that the sensor device has a free end whichis designed in such a way that the at least one septum of the at leastone compartment can be penetrated, preferably in a directionsubstantially orthogonal to the plane of the septum.

The at least one compartment containing a calibrating agent can bedesigned as a unit closed on one or both sides by septa. The at leastone septum can be joined by known techniques, such as for examplebonding, welding, screwing or gluing, to walls of the at least onecompartment.

The at least one septum is preferably configured so that the calibratingagent contained in the at least one compartment is permanently enclosed,but permits the passage of the sensory element. Furthermore it isparticularly advantageous if the at least one septum is implemented insuch a way that the sensor unit and/or the sensitive element onpenetrating the at least one septum is at the same time cleansed of thecalibrating agent. To this end it is proposed that the at least oneseptum can consist for example of single-layer or multilayer films orsheets of elastic polymers. Examples of possible polymers are PE, EVAand polyamides. The polymers that are used should be stable to ageing,chemicals and radiation, and should preferably also be FDA-compliant. Asan alternative to the aforementioned polymers composite materials,polymer blends or elastomers, such as for example a (FDA-approved)microcellular rubber film, can also be used, which can be preparedbeforehand for easier penetration, for example by providing regions ofdifferent material thickness, a (partial) perforation or the like. Inthis way a type of predetermined rupture point can be provided in arelevant septum.

The sensor unit can comprise several compartments, which are arrangedbehind one another in relation to the penetration direction of thesensor device and which are separated from one another by respectivesepta arranged therebetween. This enables for example severalcompartments to be arranged behind one another in the direction in whichthe sensor device is moved from the initial position to the end positionintroduced in the fermenter. Since the individual compartments areseparated from one another by septa, this ensures that the calibratingagents contained in the compartments cannot intermix. In addition thestripping of calibrating agents of one compartment by the septa can beensured before the sensitive element is introduced into the neighbouringcompartment with another calibrating agent.

Alternatively or in addition the sensor unit can comprise severalcompartments, which are arranged relative to one another substantiallyorthogonal to the penetration direction. With such an arrangement ofcompartments the sensor device can be withdrawn from a first compartmentand then after a feed motion to a next compartment can be introducedinto this.

So long as a plurality of compartments are provided in a sensor unit, acleaning agent can be contained in at least one of these compartments,by means of which the sensitive element of the sensor device can becleaned to remove adhering impurities in order thereby to ensure that nomeasurement value errors caused by impurities, or possibly contaminationin the reaction vessel, such as the fermenter, can occur.

In order to suppress the adherence of impurities still further, it isproposed to allocate a stripping device to the at least one compartment,which device can be penetrated by the sensor device and is designed insuch a way that impurities adhering to the sensor device, in particularadhering calibrating agent or possibly cleaning agent, are retained inthe relevant compartment with calibrating agent or possibly cleaningagent. As already mentioned above, the stripping device can be formed byat least one septum or by at least one additional stripping meansadjacent to the septum in the penetration direction, in particular asealing ring.

Preferably the calibrating unit comprises actuating means acting on theat least one sensor device, which are implemented in such a way that bymeans of the actuating means the irreversible relative movement betweenthe at least one sensor device and the at least one compartment can beeffected. As actuating means there may be used structural parts that canbe manipulated from outside the housing, and which can be joined bywidely differing types of mechanical connections to the sensor deviceand to the housing, so that as a result of the co-operation of themechanical connections an irreversible guidance of the sensor device bymeans of the actuating means takes place. Such mechanical connectionsmay for example be threads, spring-groove engagements, locking means orthe like.

The calibrating agent and/or the cleaning agent is preferably formulatedas a sterilisable viscous medium, in particular as a gel or paste. Suchcalibrating agents, in particular highly viscous agents, aredimensionally stable and, in contrast to liquids, do not run. This canbe particularly advantageous if a compartment also contains a gaseousphase. A gaseous phase present on the sensitive element can interferewith or even completely invalidate the calibration. A compressiblegaseous phase in a compartment is necessary however in order tocompensate the displacement of calibrating agent through the sensordipping into the compartment, so long as the relevant compartment isprovided with rigid walls. In such a case it is preferred that the ratioof gel phase to gaseous phase is chosen so that the sensor remainssufficiently wetted with calibrating agent in every position. In thisway it is possible to use the sensor unit in any arbitrary alignment ofthe sensor device.

If less viscous, more flowable calibrating agents or cleaning agents areto be used, it is conceivable to avoid a gaseous phase in the at leastone compartment. In order to be able to compensate the increase involume resulting from the insertion of the sensor device into the atleast one compartment, the at least one compartment can have flexiblewalls, for example in the form of a type of bellows.

The at least one calibrating agent can contain a synthetic polymer, inparticular polyvinyl alcohol or hydroxyethylcellulose, or naturalpolymers, in particular polysaccharides, as thickening agent.

According to a further aspect the invention also relates to a reactionvessel, such as a fermenter, in particular a disposable fermenter, witha reaction space and a calibrating unit, which is rigidly connected, inparticular screwed, bonded or welded, thereto with at least one of thefeatures mentioned above, wherein the reaction vessel and thecalibratable sensor unit are sterilisable or sterilised together.

By way of development it is proposed that in a reaction vessel thesensor device in the already discussed measurement readiness position isat least partly accommodated, in particular with its sensitive element,in the reaction space.

The reaction space can be separated from the sensor unit by at least oneseptum associated with the reaction vessel and/or with the sensor unit.This allows on the one hand a seal to be created between the reactionspace and sensor unit, and on the other hand provides an access for thesensor device into the reaction space on penetration of the septum.

Furthermore a method is also proposed for calibrating at least onesensor device of a sensor unit with at least one of the featuresmentioned above connected to a reaction vessel, such as a fermenter, inparticular a disposable fermenter, this method comprising the followingsteps:

-   -   a) Insertion of a sensitive element of the at least one sensor        device into a compartment of the sensor unit containing a        calibrating agent,    -   b) withdrawal of the sensitive element from the compartment,    -   c) insertion of the sensitive element into the reaction vessel        and locking the sensor device in position,        -   wherein the steps a) to c) are carried out irreversibly.

By way of development of the method, it is proposed that the steps a)and b) be carried out on at least one further compartment containing afurther calibrating agent or a cleaning agent, before executing the stepc).

On repeating the steps a) and b) on each further compartment, the atleast one sensor device is guided, if necessary temporarily stopped, sothat the sensitive element no longer comes into contact with a precedingcompartment.

The invention is described hereinafter by way of example and in anon-limiting manner with reference to the accompanying figures on thebasis of two embodiments. In the drawings:

FIG. 1 shows in a schematic and perspective exploded view a calibratablesensor unit according to a first embodiment of the invention.

FIG. 2 shows in the part-figures a) to c) the sensor unit of FIG. 1 in alongitudinal sectional view in various positions during its use.

FIG. 3 shows a schematic and perspective exploded view of a secondembodiment of the sensor unit according to the invention.

FIGS. 4 to 10 show sectional views of the sensor unit of FIG. 3 invarious positions during its use.

FIG. 11 shows a schematic plan view of the sensor unit of FIG. 3.

The invention is described in more detail hereinafter with the aid oftwo embodiments, so-called pH single-rod measuring chains beingdescribed purely by way of example as sensors. This in no way limits thesensor unit to such sensors, and other sensors can equally well beprovided for measuring further chemical and/or physical properties.Furthermore it is also pointed out that the number of sensorsillustrated in the examples of implementation, which are described withthe respective sensor unit, should likewise not be regarded as limiting,but that in addition to the illustrated sensor units with one or twosensors, more sensors may also be provided in a sensor unit. It ismoreover pointed out that not just one of the following embodiments ofthe sensor unit can be arranged on a reaction vessel, such as afermenter, in particular a disposable fermenter, but that also aplurality of such sensor units, possibly also different types of sensorunits, can be installed at different sites of a reaction vessel. Afermenter is described hereinafter as reaction vessel, but should in noway be understood as limiting.

A first embodiment of a sensor unit 10 schematically illustrated in FIG.1 comprises a sleeve-like or connecter-like housing 12, which in itslongitudinal direction defines a movement axis BA along which a sensordevice 14 can be moved. The sensor device 14 comprises at its upper enda plate-like or wing-like actuating element 16, which is arrangedoutside the housing 12 and can be gripped by a user. The actuatingelement 16 is joined to a guide sleeve 18, which can extend in thedirection BA substantially orthogonal to the actuating element 16. Inorder to seal the housing 12 a sealing element 20, for example in thiscase bellows 20, can be arranged around the guide sleeve, so as to sealthe interior of the housing 12 against the surroundings. A sensor 22 isconnected to the guide sleeve 18 and to the actuating element 16. Thissensor 22 is, as already mentioned in the introduction to thedescription of the figures, implemented as a pH one-rod measuring chain.A receiving sleeve 24 is arranged in the housing 12, and is provided soas to receive a plurality of compartments, in the present example threecompartments 26, 28 and 30. The compartments 26, 28 and 30 are separatedand sealed from one another by means of septa 32, 34 and 36. So-calledcleaning septa 38 and 40 are arranged between the compartments 28 and 30as well as in the direction BA downwards adjoining the compartment 30,which serve to retain impurities adhering to the sensor 22 duringpenetration through the relevant septum 38, 40, so that no impuritiesreach the next compartment (here the compartment 30) or subsequently thefermenter (not shown), adjoining the calibrating unit 10 in thedirection BA downwards.

The receiving sleeve 24, the housing 12 and the guide sleeve 18 aredimensioned so that the sensor device 14 can be moved relative to thereceiving sleeve 24 and to the compartments 26, 28, 30 accommodatedtherein in the direction BA from the top downwards, referred to thechosen illustration. In the movement of the sensor device 14 relative tothe receiving sleeve 24 and to the housing 12 the guide sleeve 18 isaccommodated in the radial direction between the receiving sleeve 24 andthe housing 12. On the guide sleeve 18 in the lower end regions thereare provided in particular spring-urged stop projections 42 (FIG. 2 a),which can engage in corresponding stop recesses that can be provided onan inner circumferential wall of the housing 12. In order to prevent arotation of the guide sleeve 18 about the axis BA the sleeve engages viaa projection denoted by the reference numeral 43 with a guide groove 45formed in the housing 12. Furthermore it is also pointed out that thesensor device 14 has at its upper end (facing away from the fermenter) aconnection piece 47, to which the sensor can be connected with ameasuring device or the like.

At its end associated with a fermenter (not shown; FIG. 1, lower endreferred to the direction BA), the sensor unit 10 has a plate-likefastening element 44, by means of which the sensor unit 10 can beconnected to a fermenter. Preferably the fastening element 44 is formedas a type of welded-on lip, which can be bonded or welded to thefermenter. In this connection it is particularly preferred if thewelded-on lip 44 as well as the fermenter are made of a plasticsmaterial, which may be the case in particular with so-called disposablefermenters. A screw connection or some other type of releasableconnection between the sensor unit and fermenter is also conceivable.

FIG. 2 shows in the part figures a) to c) the movement on the sensor 22from an initial position (FIG. 2 a) via an intermediate position (FIG. 2b) to a measurement readiness position (FIG. 2 c), in which the sensor22 is arranged with its lower or front sensitive region or sensitiveelement 46 in an interior (reaction space) of a fermenter 48 (reactionvessel) indicated only implicitly here.

In the initial position according to FIG. 2 a) the sensor 22 togetherwith its sensitive element 46 is located in the compartment 26, which isfilled with a calibrating agent, for example a pH buffer gel of pH 4. Inthis initial position a calibration of the sensor 22 can be carried outon the basis of the buffer gel accommodated in the compartment 26. Aftercarrying out this first calibration step the sensor 22 is moved by meansof the actuating element 16 in the direction of the fermenter 48. At thesame time the sensor 22 together with its end 50, which can beimplemented as a sharp tip, facing towards the fermenter 48 penetratesthe septum 34 separating and sealing the compartment 26 from thecompartment 28. The compartment 28 may contain a cleaning agent, so thatthe sensor 22, in particular its sensitive end 46, can be cleansed ofimpurities with calibrating agent from the compartment 26. On furthermovement of the actuating element 16 and sensor 22 together with theguide sleeve 18 towards the fermenter 48, the tip 50 penetrates thecleaning septum 38 as well as the septum 36 sealing the compartment 30,so that the sensitive element 46 is now located according to FIG. 2 b)in the compartment 30. In this position the stop projections 42 of theguide sleeve 18 engage in a locking manner with stop recesses 52provided in the housing 12. The stop recesses can also be designed inthe form of a type of annular groove as a single stop recess 52. Thestop projections 42 are preferably designed in such a way that theyengage with the stop recesses 52 so that a movement of the actuatingelement 16 and thus of the sensor 22 away from the fermenter 48 isimpossible or can be executed only by exerting a strong force. In thisway the co-operation of stop projections 42 and stop recesses 52constitutes a type of locking of the sensor device 14 relative to thecompartments 26, 28, 30. Since the stop projections 42 towards thefermenter preferably have a conically shaped circumferential surface,they can be guided inwardly from the stop recess 52 in the direction ofthe fermenter 48 under elastic radial deflection.

The compartment 30 can contain a further calibrating agent, for examplea pH 7 buffer gel, so that a further calibration of the sensor 22 can becarried out in the intermediate position illustrated in FIG. 2 b).

After this second calibration has been carried out the actuating element16 can be moved further in the direction of the fermenter 48, so thatthe sensor 22, in particular its sensitive element 46, can be movedstraight through the cleaning septum 40 and through an opening 54provided in the fermenter 48, into the interior of the fermenter 48. Inthis connection it is pointed out that also the housing 12 can have anopening 56 adjacent to the opening 54 of the fermenter 48, provided forthe passage of the sensor 22. This can likewise be closed by a septum.

As illustrated in FIG. 2 c), the stop projections 42 of the guide sleeve18 likewise engage in the illustrated end position of the sensor 22 inone or more stop recesses 52′, so that the actuating element 16 and thusthe sensor 22 cannot be moved in the direction away from the fermenter48.

It is pointed out that in the illustrated embodiment the compartments26, 28 and 30 are formed as bellows and are completely filled with therespective calibrating agent or cleaning agent, without the presence ofany gaseous phase in the relevant compartment. On penetration of thesensor 22 into the compartments these expand within the receiving sleeve24 on account of the displacement of the calibrating or cleaning agentin the longitudinal direction. It is furthermore pointed out that thereceiving sleeve 24 may have a radially inwardly pointing projection 58,on which the cleaning septum 38 is supported. The compartment 30 is thusaccommodated between this projection 58 and the lower edge of thehousing 12 forming the opening 56.

The movement of the sensor 22 and of its sensitive element 46 from theinitial position according to FIG. 2 a) to the end position according toFIG. 2 c) takes place irreversibly, so that the sensitive element 46 canbe moved in a well-defined manner from the first compartment 26 into thesecond compartment 28, the third compartment 30 and finally into theinterior of the fermenter 48. A movement of the sensor 22 away from thefermenter 48 is prevented by the engagement between the stop projections42 of the guide sleeve 18 and the stop recesses 52 and 52′ in thehousing 12. It should also be noted in this connection that the stopprojections 42 can also be accommodated in the initial positionaccording to FIG. 2 a) in a stop recess 52″, so that the sensor 22 andthe sensitive element 46 are securely held in this initial position andthe sensitive element 46 is accommodated in the buffer solution of thecompartment 26.

FIG. 3 shows a second embodiment of a sensor unit, in which structuralparts that are similar or identical to the first embodiment are denotedby the same reference numerals increased by 100.

A sensor unit 110 according to a second embodiment comprises a housing112, which is preferably implemented in the form of a connector or tube,receptacles being provided in the interior of the housing in whichcompartments 126, 126′, 128 and 128′ can be accommodated. Thereceptacles can clearly be seen for example in FIG. 11 and are providedwith the reference numerals 113 a to 113 d. As can be seen on comparingFIG. 3 and FIG. 11, the compartments 126, 126′, 128 and 128′ arearranged next to one another along a curved, preferably circular, line115. In this connection the compartments 126, 128 and 126′, 128′ formrespective groups of compartments for a respective sensor device 114,114′ (FIG. 3). Connecting passages 117 and 117′ are also providedadjacent to the receptacles 113 b and 113 d in the housing 12, throughwhich the respective sensor device 114, 114′ can be moved into anassociated fermenter.

The sensor devices 114, 114′ are accommodated in an actuating element116 and are preferably firmly connected to the latter. The actuatingelement 116 is preferably designed as a type of cap, which can be turnedrelative to the housing 112 in the direction of the arrow 119 (here forexample anti-clockwise). The rotation takes place about an axis or shaft160 connected to the housing 112. The actuating element 116 can be movedup and down, i.e. away from the fermenter and towards the fermenter,along the axial direction BA of the shaft 160. Preferably the actuatingelement 116 is pretensioned in the direction of the fermenter by meansof a spring 162.

A seal is effected between the actuating element 116 and the housing 112by means of bellows 120, and a further seal is effected between thestationery shaft 160 and the actuating element 116 by means of furtherbellows 164. In this embodiment too pH single-rod measuring chains 122for example can be used as sensors. As can be seen from FIG. 3, twosensor devices 114, 114′ are provided in the actuating element 116,which can be caused to move jointly by means of the actuating element116. It is pointed out that the sensor devices 114, 114′ can also bedifferent sensors, for example a pH sensor and a sensor for measuringthe oxygen content or the like.

The rotation of the actuating element 116 in the direction of the arrow119 (here anti-clockwise) is preferably only allowed if the actuatingelement 116 is moved upwardly against the pretensioning exerted by thespring 162. In addition the recesses 113 a to 113 d, the connectingpassages 117, 117′ are joined to one another by grooves or guides 166and 166′, so that in co-operation with the respective sleeves 118 (orsleeve 118′ not visible) surrounding the sensors 122, a rotation of theactuating element 116 in the opposite direction (here clockwise) isprevented. Through the rotational movement and the raising and loweringof the actuating element 116 the sensor devices 114, 114′ can be broughtto the respective associated compartments 126, 128 and 126′, 128′.Furthermore, in a last step the feed of the sensor device 114, 114′ tothe fermenter can take place through the connecting passages 117, 117′.

It should be noted that a welded-on lip 144 is provided on the housing112, by means of which the sensor unit 110 can be joined to anassociated fermenter, preferably a disposable fermenter. In addition thesensor devices 114, 114′ have respective connecting pieces 147, 147′ forconnection to a measuring device or the like.

The guide sleeve 118 receiving the sensor 122 has in its lower section atype of journal 168, which is guided by the edges and grooves 166, 166′.The journal 168 has an elastic locking element 170 pretensioneddownwardly and towards the fermenter, which by co-operating with guidesand grooves 166, 166′ formed in the housing 112 and with circumferentialedges of the receptacles 113 a to 113 d, can prevent a rotation of theactuating element 116 in the opposite direction to the arrow 119.

The movement sequence and the calibration procedure are describedhereinafter with reference to FIGS. 4 to 10 by the example of the sensordevice 114. Here FIGS. 4 to 10 illustrate sections running tangentiallyto the arc 115, as is shown by way of example by the sectional linesIV-IV, VIII-VIII and X-X in FIG. 11. The steps illustrated in FIGS. 5 to7 and 9 are likewise tangential sections at intermediate positions, andfor the sake of comprehension corresponding further sectional lines havebeen omitted in FIG. 11.

FIG. 4 shows the assembled sensor unit 110 in a so-called initialposition. In this initial position the sensor 122, in particular itssensitive element 146, is accommodated in the compartment 126. Thiscompartment 126 can contain a calibrating agent, for example a pH buffersolution. The compartment 126 is closed to the inside of the housing 112and sensor unit 110 by means of a septum 132 that can penetrate throughthe sensor 122. The septum 132 can also have a cleaning action, so thatwhen the sensor 122 is withdrawn from the compartment 126 impuritiesadhering to the sensor can mostly be retained in the compartment 126. Ascan further be seen from the figure, the actuating element in thisinitial position illustrated here cannot be rotated clockwise about theaxis BA, since the locking element 170 provided on the sleeve 118 and onthe journal 168 bears against an edge of the housing 112 preventing thisrotation

In order to bring the sensor 122 into operation for measurements in thefermenter 148, after carrying out a first calibration in the compartment126 the actuating element 116 can be moved upwards along the axis orshaft 160 (FIG. 3), in other words away from the fermenter 148, so thatthe guide sleeve 118 and the sensor 122 are moved upwardly together withit. After the actuating element 116 has been moved upwards by a certaindistance, a rotational movement about the axis and shaft 160 (FIG. 3) inthe direction of the arrow 119 (counter-clockwise) can take place, as isillustrated in FIG. 6, whereby the sensor 122 can be moved from thereceptacle 113 a to the receptacle 113 b (FIG. 11) along the movementline 115. In this rotational movement the locking element 170 is in aroughly horizontal arrangement on a guide edge or a groove 166, which isformed between the two receptacles 113 a, 113 b, as can be seen in FIG.6. As soon as the sensor 122 is roughly in alignment with the receptacle113 b (FIG. 7) the locking element 170 is moved on account of itselastic pretensioning into the receptacle 113 b and engages behind itsinner edge, so that a rotational movement against the direction of thearrow 119 shown in FIGS. 6 and 7 is no longer possible. After completionof the rotational movement from the first receptacle 113 a to the secondreceptacle 113 b, a lowering of the actuating element 116 takes place inthe direction of the fermenter 148, so that the sensor 122, inparticular its sensitive element 146, can be moved into the compartment128. In this feed motion of the actuating element 118 along the axis andshaft 160 (FIG. 3), the sensor 122 with its tip 150 penetrates theseptum 134 sealing the compartment 128. The compartment 128 can containa further calibrating agent or a cleaning agent, so that the sensor 122and its sensitive element 146 can be calibrated and cleaned in thedesired way.

After the calibration and cleaning step illustrated in FIG. 8 has beencarried out, the actuating element 116 can be moved again in thedirection away from the fermenter and then turned further anti-clockwiseuntil the sensor 122 is substantially in alignment with the passageopening 117. An intermediate position during the rotation can be seen inFIG. 9, and FIG. 10 shows the measurement readiness position, in whichthe actuating element is moved fully downwards through the opening 117towards the fermenter 148, so that the sensor 122 and its sensitiveelement 146 are arranged in the interior (reaction space) of thefermenter 148 (reaction vessel).

As regards designing and executing the compartments 126, 128 with rigidor elastic walls, reference is made to the introductory comments.

It should also be noted that the septa or stripping elements have, inaddition to their sealing function of the compartments and the cleaningfunction for the sensor, also a function that stabilises the sensor inits position in a respective compartment. By way of example reference ismade once more to FIGS. 1 and 2, which show a supporting ring 72arranged above the compartments 26, 28, 30, which can ensure a radialguidance of the relatively long sensor 122 in particular through thefirst two compartments 26 and 28.

Preliminary tests have already been carried out with a sensor unit 10according to the first embodiment (FIGS. 1 and 2). In the test twocompartments were filled with pH buffer gels of pH 4 and pH7, and a pHsingle-rod measuring chain with a conical glass cone was used. Theviscosities of the two calibrating gels were chosen to be relativelyhigh (>5,000 mPa/s). The pH buffer gel of pH 4 served as storage gel.The septa of the compartments consisted of a double-layered LDPE film,which was screwed with a screw plug into a thread. After 30 days'storage the pH single-rod measuring chain was calibrated in an overheadposition, not shown in the figures, in the two calibrating gels buffergel pH 4 and buffer gel pH 7 according to the procedure described withreference to FIGS. 1 and 2. A pH check measurement was then carried outin a buffer gel of pH 4 arranged separated from the compartments outsidethe calibrating unit. A very good agreement between the theoreticalvalues and the measured pH values was found in this case. In addition avery good cleaning of the pH electrodes (sensitive element 46) wasachieved by the septa. No noticeable gel residues were found on thesensor nor any leakage of gel into the reaction space (fermenter).

The sensor units 10, 110 proposed here can be firmy connected, inparticular screwed or bonded or welded, to a disposable fermenter. Thecalibrating units and in particular their calibrating agents andcleaning agents and sensors are implemented so that the fermentertogether with the calibratable sensor units attached thereto can bereliably sterilised. Accordingly conventional and proven sensors inparticular can be used with disposable fermenters without the fermenterbeing contaminated during the attachment and/or calibration of thesensors.

1. A reaction vessel comprising a reaction space, wherein the reactionvessel is configured to be connected with a sensor unit, wherein thesensor unit comprises at least one sensor device configured to becalibrated, at least one compartment containing a calibrating agent, anda housing, wherein the at least one sensor device and the at least onecompartment are accommodated movably relative to one another in thehousing which is configured to be connected to the reaction vessel,wherein the sensor unit is arranged so as to calibrate the at least onesensor device by contact with the calibrating agent before chemicaland/or physical parameters of a measurement substance are measured withthe at least one sensor device, wherein the at least one sensor deviceis further configured such that the relative movement between the atleast one sensor device and the at least one compartment isirreversible, wherein the at least one sensor device is movable relativeto the at least one compartment from an initial position in which the atleast one sensor device does not contact the measurement substance intoa measurement readiness position different from the initial position, inwhich the at least one sensor device is at least partially contactableby the measurement substance, and wherein the reaction vessel and thesensor unit can be sterilised or are sterilised jointly.
 2. The reactionvessel according to claim 1, wherein the at least one sensor device,when in the measurement readiness position, is accommodated at leastpartially, in the reaction space.
 3. The reaction vessel according toclaim 1, wherein the reaction space is separated from the sensor unit byat least one septum associated with the reaction vessel.
 4. The reactionvessel according to claim 2, wherein the reaction space is separatedfrom the sensor unit by at least one septum associated with the reactionvessel.
 5. The reaction vessel according to claim 1, wherein thereaction vessel is a fermenter.
 6. The reaction vessel according toclaim 1, wherein the reaction vessel is a disposable fermenter.
 7. Thereaction vessel according to claim 1, wherein the reaction vessel isconnected to the sensor unit by screwing, bonding, or welding thereaction vessel and the sensor unit together.
 8. The reaction vesselaccording to claim 1, wherein a sensitive element of the at least onesensor device is accommodated in the reaction space, when the at leastone sensor device is in the measurement readiness position.
 9. Thereaction vessel according to claim 1, wherein the reaction space isseparated from the sensor unit by at least one septum associated with asleeve of the reaction vessel and/or the sensor unit.
 10. The reactionvessel according to claim 2, wherein the reaction space is separatedfrom the sensor unit by at least one septum associated with a sleeve ofthe reaction vessel and/or the sensor unit.